Aminophylline Shortage and Current Recommendations for Reversal of Vasodilator Stress: an ASNC Information Statement Endorsed By

Abidov et al. Journal of Cardiovascular Magnetic Resonance (2018) 20:87 https://doi.org/10.1186/s12968-018-0510-7

REVIEW Open Access Aminophylline shortage and current recommendations for reversal of vasodilator stress: an ASNC information statement endorsed by SCMR Aiden Abidov1, Vasken Dilsizian2, Rami Doukky3, W. Lane Duvall4, Christopher Dyke5, Michael D. Elliott6, Fadi G. Hage7, Milena J. Henzlova8, Nils P. Johnson9, Ronald G. Schwartz10, Gregory S. Thomas11 and Andrew J. Einstein12*

Abstract Pharmacologic reversal of serious or intolerable side effects (SISE) from vasodilator stress is an important safety and comfort measure for patients experiencing such effects. While typically performed using intravenous aminophylline, recurrent shortages of this agent have led to a greater need to limit its use and consider alternative agents. This information statement provides background and recommendations addressing indications for vasodilator reversal, timing of a reversal agent, incidence of observed SISE with vasodilator stress, clinical and logistical considerations for aminophylline-based reversal, and alternative non-aminophylline based reversal protocols.

Overview and safe reversal of SISE from vasodilator stress during The purpose of this document is to provide cardiac imaging pharmacologic stress myocardial perfusion imaging (MPI) specialists performing vasodilator stress testing with specific with single photon emission computed tomography recommendations regarding options for the reversal of (SPECT), positron emission tomography (PET), or vasodilator stress. The timeliness of this document is cardiovascular magnetic resonance (CMR). associated with recurrent shortages of aminophylline, which has been used in most laboratories for reversal of serious Indications for vasodilator stress reversal and intolerable side effects (SISE) from vasodilator stress. ASNC 2016 imaging guidelines for SPECT nuclear cardi- This information serves as a summary of expert opinion ology procedures[1] support using aminophylline for on this topic developed by the American Society of Nuclear reversing the effects of vasodilator stress testing with Cardiology (ASNC) and endorsed by the Society for adenosine, regadenoson and dipyridamole when SISE are Cardiovascular Magnetic Resonance (SCMR). This docu- encountered. The guidelines reflect evidence that most ment covers general indications for reversal of SISE from vasodilator stress-related adverse effects are self-limiting vasodilator stress, the standard reversal procedure using and do not require reversal. Serious adverse effects can be intravenous (IV) aminophylline, and alternative options effectively aborted with IV administration of aminophyl- based on evidence and expert opinion for effective line, a xanthine derivative and a nonselective adenosine receptor antagonist [2], with the exception of seizures. * Correspondence: [email protected] Intravenous lorazepam should be the first-line interven- This article is co-published in the journals Journal of Nuclear Cardiology and tion for seizures and methylxanthine use is not recom- Journal of Cardiovascular Magnetic Resonance, and is available at https:// doi.org/10.1007/s12350-018-01548-0 and https://doi.org/10.1186/s12968-018- mended for reversal of adenosine or regadenoson effects 0510-7 respectively. under these circumstances because of the concern for 12 Department of Medicine, and Department of Radiology, Columbia possible lowering of the seizure threshold and potential University Irving Medical Center and New York-Presbyterian Hospital, 622 West 168th Street PH 10-203, New York, NY 10032, USA risk of exacerbating seizures [3], based on limited evidence Full list of author information is available at the end of the article and the preponderance of expert opinion.

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abidov et al. Journal of Cardiovascular Magnetic Resonance (2018) 20:87 Page 2 of 6

Based on the 2016 guidelines[1], indications for rever- high likelihood of ischemic heart disease, the possibility of sal of vasodilator stress using IV aminophylline (50 to a “false-negative” scan should be considered and further 250 mg intravenously at least 1 min after the tracer testing with an alternative stress agent (such as dobuta- injection) include the following: mine) should be considered. For stress CMR, a reversal agent can be given once first-pass stress perfusion images 1. Severe hypotension (systolic blood pressure (BP) have been acquired. ≤80 mmHg) or symptomatic hypotension; 2. Development of symptomatic, persistent Mobitz II Incidence of observed side effects with second degree or complete heart block; vasodilator stress 3. Significant cardiac arrhythmia (e.g. ventricular Based on published evidence, the vasodilator stressor tachycardia); agents used in current cardiology practice are safe and 4. Wheezing; have a very low observed rate of serious adverse effects 5. Severe chest pain associated with ST depression of (Table 1). Mild, easily reversible adverse effects are fre- 2 mm or greater, or ST elevation of 1 mm or quent. Perceived shortness of breath associated with rega- greater; denoson is commonly seen and does not reflect elevated 6. Signs of poor perfusion (pallor, cyanosis, cold or pulmonary capillary wedge pressure, but may reflect a clammy skin); central nervous system effect [11]. Gastrointestinal side 7. Intolerable symptoms such as nausea, vomiting, or effects are overall mild/transient and are more frequently abdominal pain. observed in patients with end-stage renal failure undergoing regadenoson stress [5, 6]. It is important for clinicians to identify patients at Table 2 [3] provides more detailed information regard- risk for SISE who may need prompt reversal of vaso- ing SISE associated with vasodilator stress agents which dilator stress agent. Those at risk include patients with essentially represents a list of indications for the reversal borderline low systolic BP (< 100 mmHg), baseline 1st procedure (with the exception of seizures). As can be or 2nd degree atrioventricular block, reactive airway seen from these data, the rate of occurrence of clinical disease, or acute coronary syndrome presentation [4]. situations matching the list of indications for reversing Patients with end-stage renal disease tend to have vasodilator stress is very infrequent. higher frequency of regadenoson-induced gastrointes- Considering combined evidence of serious adverse tinal side effects [5, 6]. effects of clinically utilized vasodilator agents and actual For CMR stress with regadenoson, in addition to SISE, guidelines-endorsed indications for aminophylline use, a pharmacologic reversal may be required for a minority of nuclear cardiology or CMR laboratory will encounter examinations (< 25%) in which rest perfusion imaging is occasional cases that require vasodilator stress reversal. needed for artifact differentiation observed on stress The rate of these cases has not been definitively assessed imaging. In such a case, given the half-life of regadenoson but it is certainly less than 10% and may be as low as 1% and the short window between stress and rest CMR perfu- based on Tables 1 and 2. With periodic shortage of ami- sion imaging, vasodilator stress reversal may be deemed nophylline, selective use of reversal agents is a reason- necessary if there is concern for residual drug effect. able alternative to routine use and does not compromise safety or effectiveness of testing. Timing of a reversal agent Few studies have examined how early following radioiso- Aminophylline-based vasodilator stress reversal: tope administration a reversal agent for vasodilator Clinical and logistical considerations stress can be administered without influencing the Despite the data demonstrating that only a fraction of results of perfusion imaging. vasodilator stress studies require a reversal procedure, The majority of myocardial uptake of the radioisotope present day cardiac imaging laboratories utilize IV occurs within 1–2 min following the radioisotope injection aminophylline much more frequently and with high [7–10]. Thus, it is important to maintain vasodilator-in- regional variability. In different clinical practices in duced myocardial hyperemic state during this period. the US, the proportion of vasodilator stress tests with However, if a very serious adverse event were to occur, the aminophylline use ranges from less than 3 to 100% vasodilator should be reversed immediately. If vasodilator [12], the latter being in an attempt to prevent any agent reversal occurs in the first minute following radio- possible adverse effects of the vasodilator stress. isotope injection, the “stress” perfusion could well be com- Randomized controlled trials demonstrate use of ami- promised. Therefore, following a premature reversal of nophylline is safe, well tolerated, and effective in vasodilator stress, if myocardial perfusion imaging is improving overall patient satisfaction with vasodilator normal or myocardial ischemia is absent in a patient with stress testing, the latter by reducing uncomfortable and Abidov et al. Journal of Cardiovascular Magnetic Resonance (2018) 20:87 Page 3 of 6

Table 1 Adverse effects of the vasodilator stressor agents (data derived from 2016 ASNC imaging guidelines for SPECT nuclear cardiology procedures [1], from Subbiah et al. [19], and from Doukky et al. [20]) Dipyridamole Adenosine Regadenoson Minor side effects (total) ~ 50% ~ 80% ~ 50% flushing 3% 35–40% 17% nonspecific chest pain 20% 25–30% 11% dyspnea 10% 20% 25% dizziness 12% 7% 7% hypotension 5% 5% 5% nausea 5% 5% 6% headache 12% 10% 29% abdominal discomfort 5–10% 5–14% 6–17% Transient conduction abnormalities: Overall 2% 8.5% 4% Transient 2nd degree AVB 1–2% 4% 0.1% Transient ST depression of ≥1mm 8% 5–7% 1–2% [20] Major side effects < 1% < 1% < 1% Complete AVB < 1% < 1% Rare Severe (> 2 mm) ST depression < 1% < 1% < 1% Fatal or nonfatal MI Extremely rare Extremely rare Extremely rare Stroke Extremely rare Extremely rare Extremely rare Seizures Rare Rare Rare Comments Symptoms may last longer Due to a short half-time, most Most adverse reactions begin (15–25 min) than with other side effects resolve in a few (< 10) soon after injection and resolve vasodilator stressors; Aminophylline seconds after discontinuation within 15 min (headaches may frequently required of the infusion; Aminophylline last up to 30 min) rarely required AVB atrioventricular block; MI myocardial infarction easily treatable symptoms [13, 14]. In pooled analysis of Alternative non-aminophylline based vasodilator two randomized but non-crossover trials including 548 stress reversal protocols patients, investigators found that perfusion did not When aminophylline is in short supply but reversal of appear to be impacted if aminophylline was adminis- SISE from vasodilator stress is indicated, alternative tered 1.5 min following Tc-99 m tetrofosmin injection reversal agents that have been shown to be effective in [15]. Until further studies are performed, a delay of 2 this setting should be used. or more minutes after tracer injection is prudent if One such agent is another xanthine derivative, theophyl- reversal is indicated. With this delay, if SISE are en- line, which has been reported to reverse adverse countered during vasodilator stress, the reversal pro- symptoms of the vasodilator stressor agents safely and cedure should be performed without concern for effectively. Since aminophylline is a salt that contains altering imaging findings. approximately 80% theophylline by weight, lower doses of To date, we do not have any published evidence whether theophylline can achieve the same reversal effects. More- routine or “prophylactic” vasodilator stress reversal using over, due to differences in concentration between ami- IV aminophylline (or any other reversal agent), regardless nophylline (25 mg/mL) and theophylline (0.8 mg/mL), it of whether or not a patient develops an adverse reaction, is becomes impractical to administer more than 50 mg of clinically beneficial. Such prophylactic use is not included theophylline as a single dose, equivalent to roughly 60 mg in the package inserts of regadenoson, adenosine, or dipyr- of aminophylline. A total of 5 published series with 215 idamole. However, it may unnecessarily complicate the per- patients support the use of IV theophylline as a vasodila- formance of vasodilator stress, introduce an intervention tor stress reversal agent [16]. In the largest such series, that may affect imaging findings if administered too soon 154 patients received theophylline for reversal of dipyrid- after tracer injection, and, at least hypothetically, increase amole; only 11 patients (7%) required a second injection, riskduetoexposuretoanunnecessarymedicalagent. and in all cases side effects or frank ischemia from dipyr- Accordingly, this approach is not recommended. idamole were successfully treated [16]. Abidov et al. Journal of Cardiovascular Magnetic Resonance (2018) 20:87 Page 4 of 6

Table 2 Serious and fatal complications of exercise and pharmacologic cardiac stress testing (rate of observed and reported events per 1000). Reproduced with permission from Dilsizian et al. [3] Exercise Dobutamine Dipyridamole Adenosine Regadenoson Gadolinium MPI MPI MPI MPI Any serious complication 0.1–3.46 2.988 0.714–2.6 0.97 Case reports NR Death 0–0.25 Case reports 0.5 Case reports Case reports NR VFib/VTach 0–25.7 0.6–1.35 NR NR NR NR Acute MI 0.038 0.3–3.0 1.0 0.108 Case reports NR Cardiac rupture Unknown Case reports NR NR NR NR High degree AVB or asystole Unknown NR Case reports Case reports Case reports NR Bronchospasm Unknown NR 1.5 0.76 Case reports NR Stroke/TIA Unknown Case reports NR NR Case reports NR AFib Unknown 5–40 NR NR Case reports NR Seizure Unknown Case reports NR 1.5 Case reports NR CIN NR NR NR NR NR NR NSF NR NR NR NR NR 0–18%a Radiation-Induced Cancer NR NR NR (theoretical) NR (theoretical) NR (theoretical) NR AVB atrioventricular block, AFib atrial fibrillation, CIN contrast induced nephropathy, MI myocardial infarction, NSF nephrogenic systemic fibrosis, NR not reported, TIA transient ischemic attack, VFib ventricular fibrillation, VTach ventricular tachycardia aRate of NSF is negligible if not zero in the current era of not administering gadolinium if the estimated glomerular filtration rate is < 30 ml/min/1.74 m2 References for entries are reported in Dilsizian et al. [3]

Another widely available methylxanthine inhibitor of ad lib (estimated 60–160 mg oral caffeine, with no exact the adenosine receptors (including adenosine 2A recep- dose available). No serious adverse effects of regadenoson tors activated by regadenoson) is caffeine. This agent is were encountered. Of the 241 patients undergoing regade- administered via either an IV or oral route. Both oral and noson stress, 152 (63%) received a reversal agent. Rates of IV caffeine were recently compared in a randomized con- complete or predominant reversal were 100% with IV ami- trolled fashion to IV aminophylline by Doran et al.[17] nophylline, 96% with IV caffeine (P=NS vs aminophylline), and were shown to provide rapid and safe reversal of and 84% with PO caffeine (P = 0.003 vs IV aminophylline). vasodilator-induced adverse effects during SPECT MPI. Of the 37 patients in the oral caffeine group, 19 assigned This study evaluated the effect of reversal agents on to oral caffeine crossed over to receive IV caffeine based patient-reported symptoms in a series of 241 consecutive on concern the symptoms might be too severe for oral patients presenting to the stress laboratory and undergo- caffeine to be effective [17]. ing regadenoson stress. Patients were randomized to IV Alternative methods of caffeine administration have also aminophylline, to 60 mg of IV caffeine over 3 to 5 min, or been used, such as buccal administration, which is to oral caffeine as either regular coffee or diet cola taken thought to be rapid and well tolerated. The only letter

Table 3 Aminophylline and Alternative Vasodilator stress reversal agents Reversal Agent HCPCS Code Formulation Cost per unit dosea Recommended dose Additional recommendations IV Aminophylline J0280 250 mg in 10 mL vial $9.92 50–125 mg; slow May repeat additional 50–125 mg manual injection as needed if the initial dose has not completely eliminated symptoms IV Theophylline J2810 400 mg in 500 mL bag $3.50 50 mg; slow manual May repeat additional 50 mg if needed injection (over 1 min) IV Caffeine Citrate J0706 60 mg in 3 mL vial $6.05 60 mg diluted in 25 cc May repeat an infusion (30–60 mg) D5W; infused over 3–5 min if neededb PO Caffeine – Caffeinated beverage – Estimated 60–160 mg; Consider switching to IV Aminophylline given as a regular coffee, or IV Caffeine if lack of complete tea or caffeinated beveragec resolution of symptoms achieved HCPCS code The Healthcare Common Procedure Coding System (HCPCS) is a collection of codes that represent procedures, supplies, products and services which may be provided to Medicare beneficiaries and to individuals enrolled in private health insurance programs. IV intravenous; mg milligram; PO oral; aCost data provided by Pete Antonopoulos, PharmD, Cook County Health, October 15, 2018. bNo definitive evidence available regarding the repeat dose. cMost regular coffees contain over 100 mg of caffeine; see data from Center for Science in the Public Interest data in Appendix 1 of 2016 ASNC Stress Protocols and Tracers guidelines.[1] For example, a 16 fluid ounce Starbucks Grande has 330 mg, and a Keurig Coffee K-Cup which makes 8 oz of coffee has 75–150 mg. A 12 oz Diet Coke has 47 mg; the Food and Drug Administration limit for cola and pepper soft drinks is 71 mg per 12 oz. Abidov et al. Journal of Cardiovascular Magnetic Resonance (2018) 20:87 Page 5 of 6

addressing this delivery method[18] did not report rates of IV aminophylline, theophylline, and caffeine. Theophylline successful reversal of side effects or ischemic electrocar- and caffeine can be substituted for aminophylline in the diographic changes, or the need for additional pharma nuclear cardiology or cardiac magnetic resonance practice cologic reversal, and thus this approach still warrants for- in the event of a shortage of IV aminophylline. Moreover, mal investigation. Direct IV injection of caffeine over a oral caffeine is typically effective in mild cases of vasodilator shorter period of 30 to 60 s has not been studied to date. stress-associated adverse reactions for most patients. These Data regarding use of the alternative reversal agents is reversal agents have been shown to be safe and effective. summarized in Table 3. Of note, calculation of the IV or Abbreviations oral caffeine dose comparable with an index dose of IV ACLS: advanced cardiac life support; ASNC: American Society of Nuclear aminophylline is challenging and not always feasible [12]. Cardiology; CMR: cardiovascular magnetic resonance; IV: intravenous; Finally, adding low-level exercise to vasodilator stress in MPI: myocardial perfusion imaging; PET: positron emission tomography; SCMR: Society for Cardiovascular Magnetic Resonance; SISE: serious and patients undergoing MPI (except patients with left bundle intolerable side effects; SPECT: single photon emission computed tomography branch block or right ventricular pacemaker), may minimize some adverse reactions during and after the Acknowledgments Not applicable. vasodilator stress, but cannot completely eliminate these negative effects [17]. Thus, reversal agents should be avail- Funding able in any stress laboratory performing vasodilator stress None. testing and medical staff should be familiar and efficient Availability of data and materials in recognizing SISE. Not applicable. While reversal of the adverse effects is an important Authors’ contributions part of safety protocols in the modern nuclear cardiology Conception and design of study: AA, AJE. Drafting the manuscript: All or cardiac magnetic resonance laboratory, vasodilator authors. Revision of manuscript: All authors. All authors read and approved induced coronary steal and ischemia in patients with the final manuscript. coronary disease may produce angina, ischemic electro Ethics approval and consent to participate cardiographic changes and/or ischemic arrhythmias. Not applicable. Therefore, approved advanced cardiac life support Consent for publication (ACLS) protocols, in addition to reversal agent adminis- Not applicable. tration, must be readily available. Similar to ischemic complications, non-cardiac severe adverse reactions, Competing interests Aiden Abidov, MD, PhD (Writing Committee Chair) - Research grant from NIH, such as severe wheezing, headache or seizures, require GE Healthcare. Vasken Dilsizian, MD - Research grant from Siemens, GE availability of a full spectrum of emergent therapeutic Healthcare. Rami Doukky, MD, MSc - Research grant from Astellas. W. Lane measures targeting these symptoms. Duvall, MD - Advisory board - Jubilant DraxImage, GE Healthcare. Christopher Dyke, MD – None. Michael D. Elliot, MD – None. Fadi Hage, MD - Research In the absence of comparative effectiveness studies, grant from Astellas, GE Healthcare. Milena J. Henzlova, MD, PhD – None. Nils P. given the chemical similarities (aminophylline is a mixture Johnson, MD - Institution has licensing/consulting agreement with Boston of theophylline and ethylenediamine), the panel recom- Scientific for the start-minimum FFR algorithm. Frequently invited by academia/ industry to speak at educational meetings/conferences on coronary physiology mends the use of IV theophylline as a first choice reversal or cardiac PET and receive travel expenses and sometimes an honorarium, agent where possible when aminophylline is not available. which I donate to my institution. Ronald G. Schwartz, MD, MS - Speakers Bureau However, shortages of these drugs have been noted in – Astellas. Gregory S. Thomas, MD - Research grant to institution - Amgen and Novartis (CHF Trials), Speakers bureau - Astellas. Andrew J. Einstein, MD, PhD tandem, so when neither is available, IV caffeine should be (Writing Committee Co-Chair)– Research grants to institution from NIH, Canon used for reversal of SISE. Medical Systems. Consultant, GE Healthcare. Drs. Abidov, Dilsizian, Doukky, Duvall, Hage, Henzlova, Johnson, Schwartz, Thomas, and Einstein served as ASNC representatives. Drs. Dyke and Elliot Summary served as SCMR representatives. Vasodilator stress related adverse reactions and complications may require implementation of a reversal procedure Publisher’sNote in approximately 1–10% of patients. There is no definitive Springer Nature remains neutral with regard to jurisdictional claims in published evidence showing any significant clinical benefit published maps and institutional affiliations. of the preventive use of vasodilator stress reversal in Author details patients undergoing vasodilator stress MPI who are 1Wayne State University and John D. Dingell VA Medical Center, Detroit, MI, 2 3 asymptomatic. Patients should be routinely advised prior USA. University of Maryland, Baltimore, MD, USA. Cook County Health, Chicago, IL, USA. 4Hartford Hospital, Hartford, CT, USA. 5Alaska Heart and to testing that rapid, safe and effective reversal of any Vascular Institute, Anchorage, AK, USA. 6Carolinas Medical Center, Charlotte, adverse effects of vasodilator stress testing is immediately NC, USA. 7University of Alabama at Birmingham and Birmingham VA Medical 8 available. Based on the available evidence, several effective Center, Birmingham, AL, USA. Friendship Center, Sarasota, FL, USA. 9University of Texas Medical School, Houston, TX, USA. 10University of and safe options for reversal of vasodilator stress-related Rochester, Rochester, NY, USA. 11MemorialCare Heart & Vascular Institute, complications/adverse reactions are available. These include University of California, Irvine, Long Beach, CA, USA. 12Department of Abidov et al. Journal of Cardiovascular Magnetic Resonance (2018) 20:87 Page 6 of 6

Medicine, and Department of Radiology, Columbia University Irving Medical Center and New York-Presbyterian Hospital, 622 West 168th Street PH 10-203, New York, NY 10032, USA.

Received: 5 November 2018 Accepted: 19 November 2018

References 1. Henzlova MJ, Duvall WL, Einstein AJ, Travin MI, Verberne HJ. ASNC imaging guidelines for SPECT nuclear cardiology procedures: stress, protocols, and tracers. J Nucl Cardiol. 2016;23:606–39. 2. Daya HA, Hage FG. Effect of aminophylline administration on the diagnostic yield of vasodilator myocardial perfusion imaging. J Nucl Cardiol. 2017;24:1579–82. 3. Dilsizian V, Gewirtz H, Paivanas N, et al. Serious and potentially life threatening complications of cardiac stress testing: physiological mechanisms and management strategies. J Nucl Cardiol. 2015;22:1198–213. 4. Rai M, Ahlberg AW, Marwell J, Chaudhary W, Savino JA III, Alter EL, et al. Safety of vasodilator stress myocardial perfusion imaging in patients with elevated cardiac biomarkers. J Nucl Cardiol. 2017;24:724–34. 5. Doukky R, Rangel MO, Wassouf M, Dick R, Alqaid A, Morales Demori R. The safety and tolerability of regadenoson in patients with end-stage renal disease: the first prospective evaluation. J Nucl Cardiol. 2013;20:205–13. 6. Rangel MO, Morales Demori R, Voll ST, Wassouf M, Dick R, Doukky R. Severe chronic kidney disease as a predictor of benefit from aminophylline administration in patients undergoing regadenoson stress myocardial perfusion imaging: a substudy of the ASSUAGE and ASSUAGE-CKD trials. J Nucl Cardiol. 2015;22:1008–18. 7. Sinusas AJ, Shi Q, Saltzberg MT, Vitols P, Jain D, Wackers FJ, et al. Technetium- 99m-tetrofosmin to assess myocardial blood flow: experimental validation in an intact canine model of ischemia. J Nucl Med. 1994;35:664–71. 8. Mousa SA, Cooney JM, Williams SJ. Relationship between regional myocardial blood flow and the distribution of 99mTc-sestamibi in the presence of total coronary artery occlusion. Am Heart J. 1990;119:842–7. 9. Glover DK, Ruiz M, Yang JY, Smith WH, Watson DD, Beller GA. Myocardial 99mTc-tetrofosmin uptake during adenosine-induced vasodilatation with either a critical or mild coronary stenosis: comparison with 201Tl and regional myocardial blood flow. Circulation. 1997;96:2332–8. 10. Watson DD, Glover DK. Overview of tracer kinetics and cellular mechanisms of uptake. In: Zaret BL, Beller GA, editors. Clinical nuclear cardiology. 4th ed. New York: Elsevier; 2010. p. 3–13. 11. Gui L, Duan W, Tian H, et al. Adenosine A2A receptor deficiency reduces striatal glutamate outflow and attenuates brain injury induced by transient focal cerebral ischemia in mice. Brain Res. 2009;1297:185–93. 12. Jolly AF, Thomas GS. Intravenous caffeine: an alternative to aminophylline to reverse adverse effects during regadenoson myocardial perfusion imaging. J Nucl Cardiol. 2017;24:1071–4. 13. Doukky R, Rangel MO, Dick R, Wassouf M, Alqaid A, Margeta B. Attenuation of the side effect profile of regadenoson: a randomized double-blind placebo-controlled study with aminophylline in patients undergoing myocardial perfusion imaging and have severe chronic kidney disease—the ASSUAGE-CKD trial. Int J Cardiovasc Imaging. 2013;29:1029–37. 14. Doukky R, Morales Demori R, Jain S, Kiriakos R, Mwansa V, Calvin JE. Attenuation of the side effect profile of regadenoson: a randomized double-blinded placebo- controlled study with aminophylline in patients undergoing myocardial perfusion imaging. “The ASSUAGE trial”. J Nucl Cardiol. 2012;19:448–57. 15. Fughhi I, Campagnoli T, Ali A, Doukky R. Impact of a regimented aminophylline administration protocol on the burden of regadenoson-induced ischemia detected by SPECT myocardial perfusion imaging. J Nucl Cardiol. 2017;24:1571–8. 16. Johnson NP, Lance Gould K. Dipyridamole reversal using theophylline during aminophylline shortage. J Nucl Cardiol. 2011;18:1115. 17. Doran JA, Sajjad W, Schneider MD, Gupta R, Mackin ML, Schwartz RG. Aminophylline and caffeine for reversal of adverse symptoms associated with regadenoson SPECT MPI. J Nucl Cardiol. 2017;24:1062–70. 18. Matangi M, Dutchak P. Buccal caffeine for the routine reversal of Persantine. J Nucl Cardiol. 2014;21:1039. 19. Subbiah R, Patil PV. Arrhythmias in vasodilator stress testing. J Nucl Cardiol. 2017;24:410–2. 20. Doukky R, Nigatu A, Khan R, et al. Prognostic significance of ischemic electrocardiographic changes with regadenoson stress myocardial perfusion imaging. J Nucl Cardiol. 2018. https://doi.org/10.1007/s12350-018-1415-4. [Epub ahead of print]